Temporal-spatial control of mitotic regulators by polySUMOylation

通过多SUMO化对有丝分裂调节因子进行时空控制

• 批准号: 10718546
• 负责人: Yanchang Wang
• 金额: $ 33.08万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718546
• 关键词: Affect; Anaphase; Biochemistry; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chromosome Segregation; Chromosomes; Complex; DNA Damage; DNA Repair; Data; Development; Disease; Ensure; Eukaryota; Event; Genome Stability; Genomic Instability; Goals; Human; Kinetochores; Knowledge; Lysine; Macromolecular Complexes; Malignant Neoplasms; Mitosis; Mitotic; Molecular; Nuclear; Nucleolar Proteins; Outcome; PLK1 gene; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Regulation; Research; Ribosomal DNA; Role; Saccharomycetales; Sumoylation Pathway; System; Testing; Translating; Ubiquitin; Ubiquitination; Work; Yeasts; biological adaptation to stress; cancer diagnosis; cancer therapy; chemical genetics; experimental study; novel therapeutic intervention; polypeptide; prevent; protein complex; protein function; repaired; response; scaffold; telophase; tool; treatment strategy; ubiquitin ligase; yeast genetics

Abstract SUMOylation is an essential post-translational modification that adds small ubiquitin-like modifiers (SUMO) to protein lysine residues. SUMOylation regulates many cellular functions, including cell proliferation, DNA repair, and stress response. Deregulation of SUMOylation contributes to genome instability and cancer development. Attachment of single SUMO to proteins often creates scaffolds to nucleate macromolecular interactions. On the other hand, attachment of chains of SUMO (polySUMOylation) often triggers protein ubiquitination and extraction from a macromolecular complex. Recent works demonstrate polySUMO-dependent relocation of damaged DNA, which facilitates damage repair. However, the function of protein polySUMOylation and its regulation during cell cycle remain poorly defined. Our long-term goal is to uncover the molecular mechanisms that control genome stability to provide fundamental knowledge that will help develop treatment strategies for diseases resulting from genome instability, such as cancer. The objective of this project is to investigate how polySUMOylation controls the relocation of two key mitotic regulators during the cell cycle: the RENT (regulator of nucleolar silencing and telophase) critical for mitotic exit, and the CPC (chromosomal passenger complex), essential for chromosome bipolar attachment. We recently found that polySUMOylation induction in yeast cells triggers relocation of these two critical mitotic regulators. Our preliminary data support the central hypothesis that polySUMOylation promotes relocation of some key mitotic regulators for successful anaphase initiation, and activation of polo-like kinase triggers polySUMOylation by phosphorylating a deSUMOylase. Our objective will be attained via the following specific aims: 1) Elucidate the mechanism of polySUMOylation-triggered nucleolar protein delocalization that promotes mitotic exit. 2) Determine how polySUMOylation of CPC subunits promotes CPC translocation. 3) Investigate the temporal control mechanism for polySUMOylation during the cell cycle. To test our hypothesis and achieve our aims, we will combine budding yeast genetics, cell biology, and biochemistry. Successful completion of this research will provide a comprehensive understanding of how polySUMOylation controls subcellular localization of protein complexes in the context of cell cycle. Given the exceptional conservation of both the SUMO system and the cell cycle machinery, principles proved in budding yeast are highly likely to translate to human and other eukaryotes. The results will have an important positive impact on the cell biology field because they will uncover new mechanisms critical for genome stability and unveil new targets for cancer diagnosis and therapy.

抽象的 sumoylation是一种必不可少的翻译后修饰 蛋白质赖氨酸残基。 Sumoylation调节许多细胞功能，包括细胞增殖，DNA修复， 和压力反应。放松管制促进有助于基因组不稳定性和癌症发展。 单一相扑与蛋白质的附着通常会产生支架对大分子相互作用的成核。在 另一方面，相扑链的附着（多糖化）通常会触发蛋白质泛素化和提取 来自大分子复合物。最近的著作表明，受损的DNA的polysumo依赖性迁移， 这有助于损坏修复。然而，蛋白质多糖苷的功能及其在细胞过程中的调节 循环的定义较差。我们的长期目标是发现控制基因组的分子机制 提供基本知识的稳定性，这些知识将有助于制定因疾病的治疗策略 基因组不稳定性，例如癌症。该项目的目的是调查多糖化如何控制 在细胞周期期间，两个关键有丝分裂调节剂的搬迁：租金（核仁沉默的调节剂和 末期）对于有丝分裂出口和CPC（染色体乘客复合物）至关重要，对染色体必不可少 双极附件。我们最近发现，酵母细胞中的多糖化诱导触发了这些细胞的迁移 两个关键有丝分裂调节剂。我们的初步数据支持多糖化的中心假设 促进某些关键有丝分裂调节剂的搬迁，以成功进行后期启动，并激活polo样 激酶通过磷酸化desumoylase触发多糖酰化。我们的目标将通过 以下特定目的：1）阐明多糖苷触发的核仁蛋白的机制 促进有丝分裂出口的离域化。 2）确定CPC亚基的多糖化如何促进CPC 易位。 3）研究细胞周期期间多糖化的时间控制机制。测试 我们的假设并实现我们的目标，我们将结合萌芽的酵母遗传学，细胞生物学和生物化学。 这项研究的成功完成将为多肿瘤化提供全面的理解 控制细胞周期中蛋白质复合物的亚细胞定位。给定特殊的 Sumo系统和细胞周期机械的保护，在萌芽酵母中证明的原理是 很可能转化为人类和其他真核生物。结果将对 细胞生物学领域，因为它们会发现对基因组稳定性至关重要的新机制 癌症诊断和治疗的靶标。